Pathophysiology of Lipid Metabolism

Introduction

Lipid metabolism is a cornerstone of cardiovascular physiology. Fats and lipoproteins not only serve as energy reservoirs but also play essential roles in cell membrane structure, steroid hormone synthesis, and signaling pathways. However, when lipid metabolism is disturbed, it can drive atherosclerosis and cardiovascular disease—the leading cause of mortality worldwide.

One of the most important and well-studied genetic disorders of lipid metabolism is familial hypercholesterolemia (FH). FH is characterized by markedly elevated plasma low-density lipoprotein cholesterol (LDL-C) from birth, leading to premature atherosclerosis and coronary artery disease. The pathophysiology of FH revolves around defects in the metabolism of LDL particles, caused by mutations in genes responsible for LDL clearance and regulation.

This article provides an in-depth exploration of the normal physiology of lipid metabolism, the molecular defects underlying FH, the mechanisms by which these defects drive atherosclerosis, and the clinical implications of these processes.

Normal Lipid Metabolism

To appreciate the derangements in FH, we must first understand normal lipid transport and metabolism.

1. Lipoprotein Classes

Lipids are insoluble in water; thus, they circulate in the blood packaged into lipoproteins—complexes of triglycerides, cholesterol, phospholipids, and apolipoproteins.

Chylomicrons – transport dietary triglycerides from the intestine.
Very-low-density lipoproteins (VLDL) – secreted by the liver, rich in triglycerides.
Intermediate-density lipoproteins (IDL) – transitional lipoproteins derived from VLDL.
Low-density lipoproteins (LDL) – cholesterol-rich particles derived from IDL; the major carriers of cholesterol in plasma.
High-density lipoproteins (HDL) – mediate reverse cholesterol transport from tissues back to the liver.

2. Role of LDL in Cholesterol Transport

LDL particles deliver cholesterol to peripheral tissues for:

Membrane synthesis.
Steroid hormone production.
Bile acid precursor formation.

Uptake occurs via the LDL receptor (LDLR) pathway:

LDLR on hepatocytes binds apolipoprotein B-100 (ApoB-100) on LDL.
LDL is internalized and degraded, releasing cholesterol.
Intracellular cholesterol regulates LDLR expression via sterol regulatory element-binding proteins (SREBPs).

3. HDL and Reverse Cholesterol Transport

HDL removes excess cholesterol from peripheral tissues and delivers it back to the liver for excretion, providing a protective role against atherosclerosis.

Familial Hypercholesterolemia: Genetic Basis

FH is primarily a disorder of LDL clearance. Mutations in specific genes impair the ability of hepatocytes to remove LDL from the circulation.

Major Genes Involved

LDLR gene (most common cause, ~80–85% cases)
- Mutations impair receptor synthesis, transport, binding, or recycling.
- Classified into 5 classes of defects:
  - Class I: No receptor synthesis.
  - Class II: Defective transport from ER to Golgi.
  - Class III: Defective binding to LDL.
  - Class IV: Defective internalization.
  - Class V: Defective recycling.
APOB gene (~5–10% cases)
- Mutations in ApoB-100 reduce LDL binding affinity for LDLR.
PCSK9 gene (~1–2% cases)
- Gain-of-function mutations in PCSK9 increase LDLR degradation, reducing receptor density on hepatocytes.
LDLRAP1 gene (rare, autosomal recessive form)
- Encodes adaptor protein necessary for LDLR internalization.

Inheritance Patterns

Heterozygous FH (HeFH): One defective allele, LDL-C typically 190–400 mg/dL.
Homozygous FH (HoFH): Both alleles defective, LDL-C >500 mg/dL, severe premature atherosclerosis.

Pathophysiology of Lipid Abnormalities in FH

1. Defective LDL Clearance

Mutations in LDLR, ApoB, or PCSK9 reduce hepatic LDL uptake.
Plasma LDL accumulates, sometimes reaching levels 2–6 times higher than normal.

2. Disrupted Feedback Regulation

Intracellular cholesterol is reduced due to poor LDL uptake.
SREBPs remain active, upregulating HMG-CoA reductase and LDLR gene expression.
Paradoxically, LDLR mutations prevent effective compensation, further aggravating hypercholesterolemia.

3. Increased LDL Production

Reduced clearance prolongs LDL half-life in plasma.
VLDL and IDL particles persist longer, contributing to LDL pool expansion.

4. Qualitative LDL Changes

LDL particles in FH may become oxidized or glycated more readily.
These modified LDLs are particularly atherogenic, promoting foam cell formation.

Atherosclerosis in Familial Hypercholesterolemia

The defining clinical problem in FH is accelerated atherosclerosis, leading to premature coronary artery disease.

Steps in FH-Driven Atherogenesis

Endothelial Dysfunction
- Elevated LDL-C increases endothelial oxidative stress.
- Nitric oxide (NO) bioavailability decreases, impairing vasodilation.
LDL Oxidation and Retention
- LDL infiltrates the intima and binds to proteoglycans.
- Oxidative modification makes LDL more immunogenic and inflammatory.
Foam Cell Formation
- Macrophages engulf oxidized LDL via scavenger receptors.
- Lipid-laden macrophages = foam cells, forming fatty streaks.
Plaque Progression
- Smooth muscle cells migrate, proliferate, and secrete extracellular matrix.
- Fibrous cap forms over lipid core.
Plaque Rupture and Thrombosis
- Vulnerable plaques rupture, exposing thrombogenic material.
- Triggers acute coronary syndromes (myocardial infarction, sudden death).

Clinical Manifestations

1. Cutaneous and Tendinous Xanthomas

Cholesterol-rich deposits in tendons (Achilles, hands) or skin.
Classic sign of FH, especially in HoFH.

2. Corneal Arcus

Gray-white lipid ring around cornea, seen in younger patients.

3. Premature Coronary Artery Disease

Myocardial infarction in 30s–40s in HeFH; even in childhood in HoFH.

4. Aortic Valve Disease

Supravalvular aortic stenosis due to lipid deposition.

Diagnostic Considerations

Clinical Criteria

Dutch Lipid Clinic Network (DLCN) score: Combines LDL-C levels, family history, physical findings, and genetic testing.
Simon Broome criteria: Widely used in the UK.

Genetic Testing

Confirms mutations in LDLR, ApoB, PCSK9, or LDLRAP1.
Useful for cascade screening in families.

Therapeutic Implications

FH treatment aims to reduce LDL-C aggressively to prevent atherosclerosis.

1. Lifestyle Modifications

Low saturated fat diet, regular exercise, smoking cessation.
Essential but insufficient alone in FH.

2. Pharmacological Therapy

Statins (HMG-CoA reductase inhibitors): First-line therapy; upregulate LDLR expression (less effective in receptor-negative mutations).
Ezetimibe: Blocks intestinal cholesterol absorption.
PCSK9 inhibitors (alirocumab, evolocumab): Monoclonal antibodies prevent LDLR degradation; highly effective in HeFH and some HoFH.
Bempedoic acid: Inhibits ATP-citrate lyase, reducing cholesterol synthesis.
Lomitapide: Inhibits microsomal triglyceride transfer protein (MTP), reducing VLDL secretion (used in HoFH).
Mipomersen: Antisense oligonucleotide targeting ApoB mRNA (limited use due to hepatotoxicity).

3. Apheresis and Advanced Therapies

LDL apheresis: Extracorporeal removal of LDL; life-saving in HoFH.
Liver transplantation: Rarely considered in refractory cases.
Gene therapy: Emerging approach targeting LDLR function.

Emerging Insights

Inflammation in FH: Beyond LDL-C, inflammation accelerates atherogenesis. Anti-inflammatory therapies (e.g., IL-1 inhibitors) may offer added benefit.
Role of Lipoprotein(a): Many FH patients also have elevated Lp(a), further increasing risk.
Precision medicine: Genetic and metabolic profiling may help tailor therapy.

Prognosis

Untreated FH: Men may develop myocardial infarction before age 50, women before 60.
Treated FH: Early and aggressive LDL-C lowering normalizes life expectancy in many HeFH patients.
HoFH: Prognosis remains poor without apheresis or advanced therapies.